Released endogenous opioid peptides regulate pain sensation, physiological stress responses and reward pathways. As such, endogenous opioids are believed to act as key modulators of the behavioral response to stress as well as drug self-administration. This proposal will assess the role of the endogenous kappa opioid system in the mediation of behavioral responses to stress and drug reward. In this proposal, we will perform a series of behavioral experiments exposing mice to the forced swim test, inducing a stress response mediated by the release of endogenous dynorphin peptides. Pilot results with C57BI/6 mice show that the mild stress induced by the forced swim test produced increases in immobility and tail-flick latency which were blocked by preadministration of the kappa opioid antagonist nor-BNl. Moreover, the increases in swimming immobility and tail-flick latency were observed in wild-type mice exposed to the forced swim stressor, but not in littermates lacking Dynorphin gene products. Future studies are planned to characterize the endogenous opioid peptides that are released in response to the swim stressor, as well as a parametric analysis to fully characterize the component of the stressor mediated by the endogenous kappa opioid system. In addition, these studies will be extended to examine the role of stress-induced endogenous kappa opioid activity in the response to rewarding drugs. Preliminary evidence shows that prior exposure of mice to a forced-swim stress induces a potentiation of the conditioned place-preference response to cocaine. In contrast, mice pretreated with nor-BNI or lacking dynorphin gene products prior to forced swimming did not show a stress-induced potentiation of cocaine conditioned place preference. Future studies with dynorphin wild type and knockout mice are planned wherein the duration of the stress effect and a parametric analysis of forced-swim stress impact on drug reward are examined by measuring the conditioned place preference for cocaine and heroin. In summary, it is expected that this data set would characterize a response to behavioral stress and drug reward regulated by the action of the endogenous kappa opioid system. A better understanding of the relationship between stress and endogenous kappa systems may lead to new insights into stress-induced relapse of drug abuse, as well as provide a new approach for therapeutic intervention in these phenomena.